Substituted 4-aminoquinazolines and a process for their production

ABSTRACT

A process for preparation of 4-aminoquinazolines and novel 4aminoquinazolines. In the process a benzonitrile derivative substituted in the 2-position by a halogen atom or alkoxy, alkylthio, aryloxy or arylthio group and in the 3- and/or 5position by an electronegative radical, is reacted with a compound corresponding to the general formula IN WHICH R represents a hydrogen atom, a hydrocarbon radical, an amino group, mono- or di-substituted amino group or a substituted sulphydryl group, in an inert solvent.

United States Patent Wagner et al.

1 Sept. 5, 1972 [54] SUBSTITUTED 4- AMINOQUINAZOLINES AND A PROCESS FORTHEIR PRODUCTION [72 Inventors: Klaus Wagner, Cologne, Buchheim; ErnstRoos, Cologne, Flittard, .both of Germany [73] Assignee: FarbenfabrikenBayer Aktiengesellschaft, Leverkusen, Germany [22] Filed: Aug. 13, 1969[21] Appl. No.: 849,868

[30] Foreign Application Priority Data Aug. 31, 1968 Germany ..P 17 95271.5

[52] US. Cl. ....260/256.4 Q, 260/41 C, 260/2565 R [51] Int. Cl. ..C07d51/48 [58] Field of Search ..260/256.4 Q, 256.5 R

[ 56] References Cited OTHER PUBLICATIONS Davoll C. A. 66, l8720g (1967)Primary Examiner-Alex Maze] Assistant Examiner-R. V. RushAtt0rneyBurgess, Dinklage & Sprung ABSTRACT in which R represents ahydrogen atom, a hydrocarbon radical, an amino group, monoordi-substituted amino group or a substituted sulphydryl group, in aninert solvent.

9 Claims, No Drawings SUBSTITUTED 4-AMINOQUINAZOL1NES AND A PROCESS FORTHEIR PRODUCTION This invention relates to substituted4-aminoquinazolines and to a process for the preparation thereof.

It is already known that 2,4-diaminoquinazolinesare obtained by reactingo-aminobenzonitriles with dicyandiamide (cf. German Patent specificationNo. 737,931, and US, Patent specification No. 2,945,859).

Unfortunately, neither of these processes has acquired any commercialsignificance because the oaminobenzonitriles required as startingmaterials are difficult to obtain.

The present invention relates to a process for the preparation ofsubstituted 4-aminoquinazolines, wherein a benzonitrile derivativesubstituted in the 2- position by a halogen atom or an alkoxy,alkylthio, aryloxy or arylthio groups and in the 3- and/or S-position byan electronegative radical, is reacted with a compound correspondingtothe general formula NH R- -NHZ (II) in which R represents a hydrogenatom, a hydrocarbon radical, an amino group, a monoor di-substitutedamino group or a substituted sulphydryl group, in an inert solvent.

Preferred benzonitrile derivatives for use in the process according tothe invention include compounds having the general formula R CN in whichX represents a halogen atom, or an alkoxy, alkylthio, aryloxy orarylthio group with preferably up to two carbon atoms in the hydrocarbonradicals, R R R and R which may be the same or different, eachrepresents hydrogen or an alkyl, alkoxy, alkylthio, aryloxy or arylthiogroup; and one or both of the radicals R and R, must represent anelectro-negative radical such as a nitro, cyano or sulphonyl group.

Examples of suitable benzonitrile derivatives may be represented by thefollowing formulas:

OzN CN OzN CN CHas 0 ON NO ON cmo OCH;

OflN CN B --C 2H5 Suitable condensation components may be represented bythe general formula in which R represents a hydrogen atom, a hydrocarbonradical, an amino group, a mono or disubstituted amino group or asubstituted sulphydryl group.vUnder the above definition, hydrocarbonradicals are linear or branched alkyl radicals, particularly those withfrom one to four carbon atoms, and aryl radicals with up to 12 carbonatoms, for example phenyl, naphthyl, tolyl and diphenyl radicals.

The following are examples of condensation components of the abovestructure: formamidine, acetamidine, propionamidine, benzamidine,guanidine, N-methylguanidine, N,N-dimethylguanidine, N-phenyl-guanidine,and N-tolyguanidine.

The 4-arninoquinazolines prepared by the process according to theinvention may be represented by the general formula R3 NHr R N R ,L.

1 (III) in which R represents a hydrogen atom, a hydrocarbon radical, anamino group, a monoor disubstituted amino group or a substitutedsulphydryl group, R and R represent electronegative groups, such asnitro, cyano or sulphonyl groups, and R and R represent hydrogen atomsand/or alkyl, alkoxy, alkylthio, aryloxy or arylthio groups.

Accordingly, the reaction is accompanied not only by elimination of thegroup X in the form of the corresponding hydrogen halide, alcohol ormercaptan, but also by cyclisation with the cyano group in theorthoposition to form the 4-aminoquinazoline derivative. Some of the4-aminoquinazolines obtained by the process have the following formulas:

J-NH: N/

NH: NH: NH: 02M k x m NC a... I! 0; NO: NO I w. Cm a NH: (i) NR1 OzN NCom NJ-NHCHa CHaO \N//\NH2 NH: NH: OzN No NJN(CHa)z N)N(CHa):

NH: NHz

oiN N NC N Ny s-cm 011.0 -s-cm N071 ON The reaction according to theinvention is carried out in the presence of inert solvents preferablypolar organic solvents, preferably at temperature of from to 160C, inparticular at temperature from 40 to 60C. Suitable solvents includemethanol, ethanol, propanol, dioxan, and dimethyl-formamide.

The process is normally carried out by reacting a solution of thecorresponding benzonitrile of general formula I, for example inmethanol, at a temperature of from 40 to. 60C, with an equimolarquantity by weight of the condensation component 11 in portions, andsubsequently stirring the reaction mixture for a while at about 60C.

The new 4-aminoquinazolines that are formed during the reaction areusually precipitated during the reaction in the form of yellow to redcrystalline compounds and may be separated by the usual methods, and thepure product may be isolated in high yields after washing with water ormethanol.

The process according to the invention is explained in detail by thefollowing general reaction equation in which the radicals R-R and Xareas defined above, and also by the following Examples:

R NH:

x1: R4 \N)R The substituted 4-aminoqunazolines are suitable for use asyellow, orange or red pigments, for example for dyeing plastics.

A mixture of 65 parts by weight of polyvinyl chloride, 35 parts byweight of di-isooctylphthalate, 2 parts by weight of dibutyl tinmercaptide, 0.5 parts by weight of titanium dioxide and 0.5 parts byweight of 2,4-diamino-6,8-dinitroquinazoline, which was finely dividedby grinding in the presence of sodium chloride and N-methylpyrrolidone,is colored on mixing rolls at 165C. An orange-red colored mass isobtained which may be used for the production of sheeting and mouldings.The color finish obtained is distinguished by its fastness both to lightand to plasticizers. Color finishes of similar shade and fastness areobtained when the other 4-aminoquinazolines obtainable by the processaccording to the invention are worked in.

EXAMPLE 1 44.6 g (0.2 mol) of 2,4-dinitro-6-cyano-anisole are dissolvedin 400 cc of methanol. A solution of 11.8 g (0.2 mol) of guanidine in100 cc of methanol is slowly added to this solution while stirring at 40to 50C, and the reaction mixture is stirred for another 3 hours at 60C.After cooling, the orange-colored product that is precipitated isremoved by filtration under suction, the filtration residue is washedwith water and then with methanol and finally dried. 2,4-diamino-6,8-dinitroquinazoline decomposing at 340C is obtained in a yield of 45 gpercent of the theoretical).

- Analysis: C H N O (250.2)

Calculated: C 38.4% H 2.4% N 33.6% 0 25.5% Found: C 38.3% H 2.8% N 34.2%0 25.5%

EXAMPLE 2 tained in a yield of 36 g (88 percent of the theoretical).AnalysiSt C8H1N5O2( l Calculated: C 46.8% H 3.4% N 34.2% 0 15.6%

Found: C 47.1% H 3.7% N 34.8% 015.5%

EXAMPLE 2a If 2-cyano-4-nitrochlorobenzene is used as the startingproduct instead of 2-cyano-4-nitro-anisole, the 2,4-diamino-6-nitroquinazoline is obtained in a yield of 75 of thetheoretical.

EXAMPLE 3 20.3 g (0.1 mol) of 2,4-dicyano-6-nitro-anisole are dissolvedin 250 cc of methanol. A solution of 4.4 g (0.1 mol) of formamidine in50 cc of methanol is then added in portions to the resulting solutionwhile stirring at 40 to 50C. The reaction mixture is then stirred foranother 2 hours at 60C, and left to cool, and the yellow-colored productthat is precipitated is removed by filtration under suction.

After washing with water and methanol, 4-amino 6-cyano-8-nitroquinazoline is obtained in a yield of 12 g (56 percent ofthe theoretical). This compound crystallises from aqueous dirnethylformamide in the form of pale yellow needles melting at temperaturesabove 360C.

Analysis: C l-l N O 21 5. l calculated: C 50.2% H 2.3% 0 14.9% N 32.6%Found: C 50.1% H 2.7% 015.5% N 32.1%

EXAMPLE 4 22.3 g (0.1 mol) of 2,4-dinitro-6-cyano-anisole are dissolvedin 200 cc of methanol, and a solution of 12.0 g (0.1 mol) of benzamidinein 100 cc of methanol is added in portions to the resulting solutionwhile stirring at 40 to 50C. The reaction mixture is stirred for another3 hours at 60C, and left to cool and the resulting small coppery needlesremoved by filtration under suction. After washing with water andmethanol, 2- phenyl-4-amino-6,8dinitroquinazoline melting at 329C isobtained in a yield of 22 g (71percent of the theoretical).

Analysis: C H N O (31 1.2) Calculated: C 54.0% H 2.9% O 20.6% N 22.5%Found: C 53.8% H 3.0% O 20.9% N 22.5%

What we claim is:

1. A process for the preparation of substituted 4- aminoquinazoline,wherein a benzonitrile derivative of 50 the formula:

in which:

x represents halogen, methoxy or ethoxy,

R and R each represents hydrogen, methyl or R JL -NHz (ll) in which R ishydrogen, alkyl of up to four carbon atoms, amino, mono-or di-methylsubstituted amino, a carbocyclic aryl radical of up to 12 carbon atoms,or methyl sulphydryl, in an inert solvent.

2. A process as claimed in claim 1 wherein the compound of formula (II)is forrnamidine, acetamidine, propionamidine, benzamidine, guanidine,N-methylguanidine, N,N-dimethyl-guanidine, N-phenyL guanidine orN-tolylguanidine.

3. A process as claimed in claim 1 wherein reaction takes place at atemperature from 20 to C.

4. A process as claimed in claim 3 wherein the temperature is from 40 to60C.

5. A process as claimed in claim 1 wherein the solvent is methanol,ethanol, propanol, dioxan or dimethyl formamide.

6. A substituted 4- aminoquinazoline of the formula:

R3 IIIH:

R R4 \NJR in which:

R, and R each represents hydrogen, methyl or methoxy R, and R, eachrepresent nitro, cyano, methyl sulphonyl or phenyl sulphonyl,

R is hydrogen, alkyl of up to four carbon atoms, amino, mono ordi-methyl substituted amino, a carbocyclic aryl radical of up to 12carbon atoms, or methyl sulphydryl.

7. 2,4-diamino-6,8-dinitroquinazoline.

8. 4-amino-6-cyano-8-nitroquinazoline,

9. 2phenyl-4-amino-6,8-dinitroquinazoline.

Patent No. 3,689,489 Dated September 5, 1972 lnvehtofls) Klaus Wagnerand Ernst Roos It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Col. 2, line 20, insert:

O N CN NC l NC CN CN Signed and sealed this 13th day of March 1973(SEAL) Attest? EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Commissioner ofPatenfq Attesting Officer

2. A process as claimed in claim 1 wherein the compound of formula (II)is formamidine, acetamidine, propionamidine, benzamidine, guanidine,N-methylguanidine, N,N-dimethyl-guanidine, N-phenylguanidine orN-tolylguanidine.
 3. A process as claimed in claim 1 wherein reactiontakes place at a temperature from 20* to 160*C.
 4. A process as claimedin claim 3 wherein the temperature is from 40* to 60*C.
 5. A process asclaimed in claim 1 wherein the solvent is methanol, ethanol, propanol,dioxan or dimethyl formamide.
 6. A substituted 4- aminoquinazoline ofthe formula:
 7. 2,4-diamino-6,8-dinitroquinazoline. 8.4-amino-6-cyano-8-nitroquinazoline, 9.2-phenyl-4-amino-6,8-dinitroquinazoline.